Impaired wound healing is a major clinical problem, and currently available treatment options often fail to fully repair tissue. Negative pressure wound therapy (NPWT) is a clinically used treatment that applies a biomaterial scaffold and negative pressure to mechanically stimulate dermal wounds. However, the mechanisms underlying NPWT remain poorly understood, and treatment still fails in a significant percentage of patients. Our previous work has established that topographical properties of biomaterials modulate the function of macrophages, essential innate immune cells that are involved in both advancing and resolving inflammation, and promoting tissue repair. More specifically, surfaces that cause macrophage elongation potentiate their response to wound healing cytokines, and protect cells from inflammation. Interestingly, cell elongation has been shown to cause profound changes in the epigenetic state of several cell types including stem cells and adult mesenchymal cells, but the role of epigenetics in biomaterial- induced macrophage polarization remains completely unknown. In this study, we propose to investigate the epigenetic regulation of macrophages in response to biomaterials structure during NPWT. We hypothesize that the structure of the biomaterial scaffold modulates the macrophage response through changes in the epigenome. We propose to test this hypothesis by: (1) investigating the effect of biomaterial structure on wound cytokines and cellular infiltrate in patients undergoing NPWT, and characterize the cellular transcriptomic and epigenomic landscapes, and (2) examine the effect of biomaterial structure on human macrophage polarization and epigenome in vitro, and screen the effects of a library of epigenetic modifiers on the biomaterial-induced macrophage response. The long-term goal of the proposed work is to better understand regulation of macrophages by the structure of biomaterials, in order to develop new strategies to promote wound healing and tissue regeneration.